Project Summary/Abstract Deep brain stimulation (DBS) in the region of the globus pallidus (GP) or subthalamic nucleus (STN) has been demonstrated to provide clinically meaningful improvements in motor function and improve patient quality of life in people with Parkinson?s disease (PD). While the STN is the typical target of choice at most neurosurgical centers, there has been a resurgence of interest in selecting the GP as a target. This interest is based on evidence that the overall clinical effects are comparable to those of STN DBS, but GP DBS may have fewer neuropsychological side-effects and affords greater flexibility for programming and adjustment of medications. Yet, there is considerable variability in response to GP DBS across patients, levodopa dose typically remains high, and, like STN DBS, is it ineffective for levodopa-resistant motor features such as postural instability, gait disturbances and freezing of gait. We argue that significant improvements in the efficacy of GP DBS can be gained through an increased understanding of the mechanisms, locations and pathways mediating the motor effects of DBS in the human pallidum. The premise of this project is that the motor effects of conventional GP DBS are compromised by a balance between the need to suppress levodopa-induced dyskinesias (akinetic) and reduce bradykinesia (prokinetic). We will test the hypothesis that the mechanisms and locations mediating these ?opposite effects? are in functionally and topographically separate regions of the GP. This hypothesis will be tested by conducting a systematic study of the effects of GP stimulation location on both levodopa- responsive (rigidity and bradykinesia) and levodopa-resistant (balance, gait, freezing) motor features of PD (Aim 2), and the topography of movement-related oscillatory activity within the pallidum (GPi and GPe) and STN by recording local field potentials in people with chronically implanted electrodes (Aim 3). State-of-the-art high-field MRI (7T) and patient-specific tractography-activation models will be used to focus stimulation to the region of interest (ventral GPi, dorsal GPi, ventral GPe) and estimate the pallidofugal pathways activated by stimulation (Aim 1). The results of these experiments will provide critical information about the stimulation location and axonal pathways mediating improvement or deterioration of motor signs with GP DBS, the neurophysiological biomarkers of disordered movement, and how these biomarkers are changed by medication and DBS. This knowledge can be translated to the next generation of DBS devices that provide current steering and closed-loop control to provide optimal therapeutic outcomes.